rs34278797

Positions:

• chr16-88841898-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001323543.2(GALNS):​c.-238C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,612,518 control chromosomes in the GnomAD database, including 477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (50 hom., cov: 33)
  • Exomes 𝑓: 0.024 (427 hom.)
• Consequence: GALNS NM_001323543.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.002116
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.902

Genes affected

GALNS (HGNC:4122): (galactosamine (N-acetyl)-6-sulfatase) This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder. [provided by RefSeq, Jul 2008]

GALNS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 16-88841898-G-A is Benign according to our data. Variant chr16-88841898-G-A is described in ClinVar as [Benign]. Clinvar id is 256333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88841898-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0194 (2948/152278) while in subpopulation NFE AF= 0.0295 (2008/68014). AF 95% confidence interval is 0.0284. There are 50 homozygotes in gnomad4. There are 1412 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNS	NM_000512.5	c.318C>T	p.Asn106Asn	splice_region_variant, synonymous_variant	3/14	ENST00000268695.10	NP_000503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNS	ENST00000268695.10	c.318C>T	p.Asn106Asn	splice_region_variant, synonymous_variant	3/14	1	NM_000512.5	ENSP00000268695.5

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2946 AN: 152160 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0184 AC: 4535 AN: 245878 Hom.: 68 AF XY: 0.0188 AC XY: 2506 AN XY: 133552

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00499

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0237 AC: 34632 AN: 1460240 Hom.: 427 Cov.: 31 AF XY: 0.0235 AC XY: 17081 AN XY: 726318

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00453

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0275

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0194 AC: 2948 AN: 152278 Hom.: 50 Cov.: 33 AF XY: 0.0190 AC XY: 1412 AN XY: 74454

Gnomad4 AFR AF: 0.00631

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0295

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0264 Hom.: 117

Bravo AF: 0.0190

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2019	Variant summary: GALNS c.318C>T (p.Asn106Asn) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.018 in 245878 control chromosomes in the gnomAD database, including 68 homozygotes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) phenotype (0.002), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.318C>T in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x Benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2017	- -

Mucopolysaccharidosis, MPS-IV-A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	This variant is associated with the following publications: (PMID: 9298823, 22521955) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 21, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.1
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34278797; hg19: chr16-88908306; COSMIC: COSV51938701; COSMIC: COSV51938701;